AB0904 BELIMUMAB FOR THE TREATMENT OF INTERSTITIAL LUNG DISEASE ASSOCIATED WITH SYSTEMIC SCLEROSIS: A PHASE 2/3, RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL
Authors: C. P. Denton, R. Spiera, D. Jörg, D. Khanna, M. Kreuter, M. Kuwana, E. Volkmann, J. Cotic, O. Raji, A. Hammer, C. Zeccin, A. Van Maurik, J. M. Olaiz, W. Fahy, R. Tomlinson, D. Dastros-Pitei, S. Nihtyanova, E. Irving, T. Maher
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> There is a breadth of evidence supporting a key role for abnormal B-cell function in the pathogenesis of systemic sclerosis and associated interstitial lung disease (SSc-ILD) <sup>[1,2]</sup>. A previous pilot study investigated the efficacy of belimumab, a recombinant human immunoglobulin G1 lambda (IgG1λ) monoclonal antibody that binds to and neutralises B-lymphocyte stimulator (BLyS) subsequently inhibiting the survival of B cells <sup>[3]</sup>, in reducing modified Rodnan skin score (mRSS) in 20 patients with SSc <sup>[4]</sup>. Belimumab is well tolerated and is approved for the treatment of patients with active systemic lupus erythematosus and active lupus nephritis receiving standard therapy <sup>[5]</sup>. We hypothesise that by reducing the number of B cells and dampening B-cell effector functions in the circulation and tissue, belimumab will reduce inflammation and fibrosis across multiple organ systems in patients with SSc. This will result in the stabilisation of, and/or reduction in, lung function decline and skin thickening in SSc, and improvements in patients' quality of life. <h3>Objectives</h3> To present the design of a randomised controlled trial that will evaluate the efficacy and safety of subcutaneous (SC) belimumab versus placebo in adult patients with SSc-ILD. <h3>Methods</h3> In this global, parallel-group, Phase 2/3, randomised, double-blind, placebo-controlled, two-arm, 52-week study (GSK Study 218224), eligible adults with a documented diagnosis of SSc and ILD (as confirmed by high-resolution computed tomography) will be randomised 1:1 to receive either belimumab 200 mg SC weekly (Arm 1), or matching SC placebo weekly (Arm 2), for 52 weeks (<b>Figure 1</b>). Participants will be permitted to continue their stable doses of standard therapy throughout the study. The primary endpoint of the study is absolute change from baseline in forced vital capacity (ml) at Week 52. Key secondary endpoints, analysed at Week 52, include: absolute change from baseline in mRSS, absolute change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score, and SSc progression or death. Patient-reported outcomes (listed in the <b>Figure 1</b>) will also be assessed. A comprehensive biomarker approach will be implemented to evaluate the belimumab modulating effects on key biological processes involved in SSc pathogenesis (fibrosis and inflammation) in circulation and in skin biopsies. Safety will be monitored throughout the study. <h3>Results</h3> Target sample size is planned to be approximately 300 patients, with 150 patients per arm. <h3>Conclusion</h3> We present the design of a global Phase 2/3 study that will test the efficacy and safety of SC belimumab in patients with SSc-ILD. Together, the study endpoints enable the assessment of the efficacy of belimumab on a broad range of disease manifestations, disease progression, and impact on patient burden and survival. <h3>References</h3> [1]Thoreau B et al. <i>Front Immunol</i> 2022;13:933468 [2]Ebata S et al. <i>J Dermatol</i> 2022;49:179–83 [3]Huang W et al. <i>JCI Insight</i> 2018;3:e122525 [4]Gordon JK et al. <i>Arthritis Rheumatol</i> 2018;70:308–16 [5]GSK. Benlysta US prescribing information. 2022 [6]van den Hoogen F et al. <i>Ann Rheum Dis</i> 2013;72:1747–55 <h3>Acknowledgements</h3> Study funded by GSK (GSK Study 218224). Medical writing support was provided by Olivia Hill, MPharmacol, Fishawack Indicia Ltd, UK, part of Fishawack Health, and was funded by GSK. <h3>Disclosure of Interests</h3> Christopher P Denton Speakers bureau: Janssen; Boehringer Ingelheim, Consultant of: GSK, CSL Behring, Boehringer Ingelheim, Merck, Roche, Sanofi, Grant/research support from: GSK, CSL Behring, Inventiva, Horizon, Robert Spiera Consultant of: GSK, Regeneron, Abbvie, Sanofi, Chemocentryx, Novartis, Galderma, Vera, Chemomab, Boehringer Ingelheim, BMS, Grant/research support from: Roche-Genentech, AstraZeneca, GSK, Kadmon, Boehringer Ingelheim, Chemocentryx, Corbus, Formation Biologics, Novartis, Inflarx, Principia, Distler Jörg Speakers bureau: AbbVie, AstraZeneca, Bayer Pharma, Boehringer Ingelheim, Janssen and UCB, Consultant of: AbbVie, Active Biotech, Anamar, ARXX, AstraZeneca, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, Janssen, Novartis, Pfizer, and UCB, Grant/research support from: Anamar, ARXX, BMS, Bayer Pharma, Boehringer Ingelheim, Cantargia, Celgene, CSL Behring, Galapagos, GSK, Inventiva, Kiniksa, Sanofi-Aventis, Tanabe-Mitsubishi RedX, UCB, Employee of: JHWD is stock owner of 4D Science and Scientific Lead of FibroCure, Dinesh Khanna Speakers bureau: Janssen, Consultant of: Actelion, Amgen, Boehringer Ingelheim, GSK, Horizon, Janssen, Prometheus, Talaris, Grant/research support from: BMS, Pfizer, Boehringer Ingelheim, Michael Kreuter Speakers bureau: Boehringer Ingelheim, Roche, Consultant of: Boehringer Ingelheim, Roche, GSK, Grant/research support from: Boehringer Ingelheim, Roche, Masataka Kuwana Speakers bureau: Abbvie, Asahi-Kasei, Astellas, Boehringer Ingelheim, Chugai, Eisai, MBL, Mochida, Nippon Shinyaku, Ono Pharmaceuticals, Tanabe-Mitsubishi, Consultant of: AstraZeneca, Boehringer Ingelheim, Chugai, Corbus, GSK, Horizon, Tanabe-Mitsubishi, Grant/research support from: Boehringer-Ingelheim, Elizabeth Volkmann Speakers bureau: Former member of speakers bureau for Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Roche, GSK, Galderma, CLS Behring, Grant/research support from: Boehringer Ingelheim, Kadmon, Horizon, Prometheus, Jasna Cotic Employee of: GSK, Olaide Raji Employee of: GSK, Anne Hammer Shareholder of: GSK, Employee of: GSK, Chiara Zeccin Shareholder of: GSK, Employee of: GSK, Andre van Maurik Shareholder of: GSK, Employee of: GSK, Jose Miyar Olaiz Shareholder of: GSK, Employee of: GSK, William Fahy Employee of: GSK, Ryan Tomlinson Shareholder of: GSK, Employee of: GSK, Daniela Dastros-Pitei Shareholder of: GSK, Employee of: GSK, Svetlana Nihtyanova Shareholder of: GSK, Consultant of: Roche, Employee of: GSK, Elaine Irving Employee of: GSK, Toby Maher Speakers bureau: BI, Roche/Genentech,United Therapeutics, Consultant of: BI, Roche, AZ, BMS, GSK, Pfizer, Sanofi, United Therapeutics, Grant/research support from: AZ, GSK.